Parkinson's disease (PD) is a degenerative disorder of the central nervous system. The motor symptoms of Parkinson's disease result from the death of dopamine-generating cells in the substantia nigra, a region of the midbrain; the cause of this cell death is unknown. By the time clinical symptoms of PD become evident, approximately 70-80% of striatal dopaminergic neurons have been lost. Early in the course of the disease, the most obvious symptoms are movement-related. Later, cognitive and behavioural problems may arise, with dementia commonly occurring in the advanced stages of the disease. However, while dopaminergic treatment is able to effectively treat the motor symptoms at the early stages of the disease, it is not a satisfactory treatment as its efficacy wears off in the later stages of disease and its prolonged use leads to motor complications.
The cardinal motor symptoms of Parkinson's disease (PD), bradykinesia, akinesia and resting tremor result from a decrease in striatal DA content which causes an imbalance in the neuronal circuits.
DA (Dopamine) replacement therapies using the DA precursor L-dihydroxyphenylalanine (L-Dopa) or dopamine (D)2/3 receptor agonists are the mainstay of current treatment strategies. However, such treatments manage the primary disease clinical symptoms only and do nothing to treat the underlying causes of the disease, i.e. the progressive loss of dopaminergic cells. Instead, they can complicate the situation due to the induction of abnormal involuntary movements (AIMs) or dyskinesia. Furthermore, the long-term treatment with L-Dopa is accompanied by unpredictable fluctuations of its effects. Novel strategies are therefore needed to treat the motor symptoms, to ameliorate or prevent dyskinesia and also to delay, prevent or reverse dopaminergic neuronal loss. Thus, therapeutic agents interfering with one or ideally with several of these events could potentially lead to a novel class of drugs perhaps with disease modifying properties for PD.
These novel drugs are expected to be as efficacious as L-Dopa but should not induce motor fluctuations or cross-sensitize with dopaminergic treatment.
In the early stages of PD, L-Dopa is metabolised to dopamine which is stored in surviving presynaptic dopaminergic terminals in the striatum (serving as storage and buffer). Its release is controlled if feed-back loops are intact. However, as more and more terminals are lost, the storage and buffering capacity for dopamine is lost and the duration of L-Dopa's effect shortens. Thus, the oral intake and subsequent pulsatile exposure of the basal ganglia provokes peak-dose dyskinesia and or motor fluctuations. Once the nigral degeneration has developed to a level that motor symptoms occur, a single injection of L-Dopa is sufficient to establish a response which is called ‘priming’ (Morelli et al., 1987; Delfino et al., 2004): Once L-Dopa has been administered and induced dyskinesia, each subsequent drug exposure will provoke that response—even if it had not been administered for several weeks. The weak NMDA (N-methyl-d-aspartate) receptor antagonist amantadine can reduce dyskinesia intensity, suggesting that over-activity of glutamatergic inputs in the basal ganglia is involved in priming and dyskinesia (Blanchet et al., 1998). Clinical and preclinical studies provide evidence of altered glutamatergic function in the striatum in dyskinetic animals and patients, including changes in expression, phosphorylation and synaptic organization of glutamate receptors (Chase et al., 2000). Furthermore, NMDA receptors containing NR2B subunits are enriched in the striatum and there is evidence that AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptor antagonists can also suppress dyskinesia (Bibbiani et al., 2005). These data seem to indicate that dyskinesia involves an abnormal glutamatergic corticostriatal input.
In order to reverse established dyskinesia or to prevent dyskinesia from occurring in the first place, one approach would be to replace dopaminergic treatment early on in the therapy. Due to their unique distribution within the basal ganglia and their interactions with dopamine-related intracellular signalling cascades, A2A antagonists and NR2B-subunit selective NMDA antagonists have been developed. However, clinical trials with A2A antagonists (Istradefylline, Mizuno et al. 2010) or NR2B antagonist (Traxoprodil, Nutt et al., 2008) as treatments in PD patients did not show the expected efficacy.
As already mentioned, priming is classically defined as the process by which the brain becomes sensitized such that administration of a dopaminergic therapy modifies the response to subsequent dopaminergic treatment. Priming is induced by acute dopamimetic treatment in a denervated brain.
The unilateral 6-hydroxydopamine (6-OHDA)-lesioned rat model may represent a quantitative model of priming. Such 6-OHDA-lesioned rats chronically treated with dopaminergic drugs (L-Dopa or dopamine agonists) develop a progressive increase of contralateral rotations (i.e. away from the side of the lesion), which is called “behavioural sensitization”. In this model, administration of a so-called ‘priming” dose of DA receptor agonist sensitizes the animal to the effect of a subsequent challenge with DA agonists.
A phenomenon of “cross-sensitization” may be observed when a subject becomes sensitized to substance different from the substance to which the subjects is already sensitized.
Cross-sensitization has already been observed between caffeine- and I-dopa-induced behaviours in hemiparkinsonian mice (Yu et al., 2006).
Adenosine receptors represent a subclass of the group of purine nucleotide and nucleoside G protein-coupled receptors known as purinoceptors; the main pharmacologically distinct adenosine receptor subtypes are known as A1, A2A, A2B, and A3. The dominant adenosine receptor subtypes in the brain are A1 and A2A. While the A1 adenosine receptor subtype is found throughout the brain at high density, the distribution of the A2A receptor is more restricted; it is found at high density in the striatum (caudate-putamen, nucleus accumbens, olfactory tubercule), where it is co-localized with the dopamine D2 receptor on striatopallidal output neurons. The discrete localization of the A2A receptor within the striatum and its ability to functionally antagonize the actions of the D2 receptor has led to the suggestion of the potential utility of A2A receptor antagonists for the symptomatic treatment of Parkinson's disease (PD).
N-methyl-D-aspartate (NMDA) receptors are heteromeric assemblies of subunits. Two principal subunit families are designated NR1 and NR2. The NR2 subunit family is divided into four subunit types which are: NR2A, NR2B, NR2C, NR2D which display different physiological and pharmacological properties such as ion gating, magnesium sensitivity, pharmacological profile, and in anatomical distribution.
While NMDA receptor inhibition has therapeutic utility primarily in the treatment of pain and neurodegenerative diseases, there are significant liabilities to many available NMDA receptor antagonists that can cause potentially serious side effects. The more discrete distribution of the NR2B subunit in the central nervous system may support a reduced side-effect profile of agents that act selectively at this site. However, even selective NR2B antagonists may exhibit low affinity towards the NR2B subunit of the NMDA receptor. Also, some NR2B antagonists which are said to be NR2B selective might not be entirely specific.
Hauber and Munkle (1996) alleged that the anti-cataleptic effects of the NMDA receptor antagonists CGP37849 (competitive) and dizocilpine (MK-801, non-competitive) may be potentiated by co-administration of the non-selective adenosine receptor antagonist/phospho-diesterase inhibitor theophylline.